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Diagnosis of HIV infection in early infancy generally relies on detection of HIV proviral DNA by PCR. However, many of the HIV DNA PCR assays currently in use either are not optimized or have not been validated for diagnosis of infection with non-subtype B HIV. We report the case of an HIV-infected African immigrant infant with subtype C HIV infection who tested negative repeatedly by HIV DNA PCR. Clinicians should be aware of this particular limitation of HIV DNA PCR assays, because it is likely that an increasing proportion of the HIV-infected infants seen in US centers will be infected with non-subtype B HIV.Current United States guidelines recommend HIV DNA PCR testing of all HIV-exposed infants at birth, 1 to 2 months and 3 to 6 months of age at a minimum. 1, 2 The CDC 3 states that HIV infection can be reasonably excluded on the basis of two or more negative HIV DNA PCR tests, both of which are performed at or after 1 month of age and one of which is performed at or after 4 months of age. We recently evaluated an HIV-exposed African immigrant infant who would have been declared presumptively uninfected with HIV had additional HIV diagnostic testing not been performed.The 8-month-old female infant of a Sudanese mother was evaluated for possible HIV infection. The mother reportedly had tested positive for HIV before her immigration to the US. Neither the mother nor the infant had received antiretroviral treatment of any kind. The infant had been exclusively breast-fed since birth. The physical examination was entirely normal. Two blood specimens were collected 2 weeks apart and sent to a national reference laboratory for HIV DNA PCR tests, both of which were negative. However, HIV RNA PCR tests (Amplicor HIV-1 version 1.0; Roche) performed on the same blood specimens were positive (6672 copies/ml and 44 593 copies/ml). The first HIV RNA PCR test was obtained only because arterial puncture had been required, and there was a desire to obtain the maximum possible amount of information. The absolute CD4+ count was 4644/μl (27%). Subsequent testing of the infant’s HIV isolate revealed that it was HIV subtype C.The HIV DNA PCR assay is the preferred diagnostic test for HIV infection in infants vertically exposed to the virus. 1 The sensitivity of the test ranges from ∼50% in the first days of life to 96 to 98% thereafter. 4, 5 Some studies suggest that the HIV RNA PCR assay might be useful for diagnosis of HIV infection in infants, but the test is not approved for this purpose. Essentially all studies of HIV DNA PCR and HIV RNA PCR for diagnosis of HIV infection in infancy have been performed in Western countries where HIV subtype B predominates.Several reports have highlighted the unreliability of HIV RNA PCR for evaluating individuals with non-subtype B HIV infection. 6 Relatively less attention has been paid to the sensitivity of HIV DNA PCR for diagnosis of non-subtype B HIV infection. In the present case we believe that the repeatedly negative HIV DNA PCR test, as well as the relatively low positive reading on the HIV RNA PCR assay, is attributable to infection with HIV subtype C. Most of the HIV DNA PCR assays in use in US laboratories have not been optimized or validated for non-subtype B HIV. The reference laboratory responsible for HIV testing in the present case uses an HIV DNA PCR assay with primers created in house. Even assays using commercially obtained PCR primers (e.g.